This application addresses broad Challenge Area (15) Translational Science, and specific Challenge Topic 15-DE-107: Metagenomics of the Oral Microbiome in Health and Disease. Consistent with the goals of the American Recovery and Reinvestment Act, this research will create multiple new jobs and involve state-of-the-art approaches to address 21st century scientific issues. We propose to use state-of-the-art metagenomic approaches to study the microbiome of the widespread human disease, chronic periodontitis. There is almost no information about the microbial community of this disease at the metagenomic level. The Human Microbiome Project (HMP) is addressing the metagenome of periodontal health, and the studies proposed here will complement and leverage the HMP by investigating the subgingival microbiome of chronic periodontitis prior to and after treatment. Our goal is to identify functional metagenomic signatures of the microbial community that differentiate periodontal health and disease. We define metagenomic signatures as genes, DNA regulatory motifs, pathogenic elements, and functional pathways or interactions. In this study, we plan to first determine whether there are metagenomic signatures that differentiate periodontal health and disease, and whether they are related to the pathogenesis of the disease, by comparing the metagenomes from sites of chronic periodontitis before and after treatment. Once we identify such metagenomic signatures, we will validate them in a different sample set by assessing the relative abundance of selected metagenomic signature DNA in the microbiomes of health and disease states. This study will define the microbial genetic elements that distinguishes chronic periodontitis from health, will provide a foundation for understanding the molecular mechanisms of chronic periodontitis, and will provide for the development of innovative clinical approaches to diagnosing, preventing and managing the disease. The research proposed in this application focuses on understanding which microbial genes found in bacteria in the pocket between the gums and the teeth contribute to chronic gum disease, a common human infection that affects about a third of US adults. We will identify microbial genetic signatures associated with gum disease that are not found in healthy microbial communities. These genetic signatures will provide important information that can be used to improve the diagnosis, prevention and treatment of periodontal (gum) diseases.